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Immunology of the maternal-fetal interface

Vikki M Abrahams, PhD
Section Editors
E Richard Stiehm, MD
Charles J Lockwood, MD, MHCM
Deputy Editor
Elizabeth TePas, MD, MS


In pregnant women, local adaptation of the maternal immune system allows for successful coexistence between the mother and the semi-allograft that is the fetus/placenta expressing both maternal (self) and paternal (nonself) genes [1-4]. Cytotoxic adaptive immune responses are diminished, bypassed, or even abrogated, while regulatory adaptive immunity is enhanced [5,6]. By contrast, innate (natural) immunity remains intact, serving two purposes: one, to continue to provide host defense against infection, and two, to interact with fetal tissues to promote successful placentation and pregnancy [4,7-10].

An introduction to the immunology of pregnancy and the maternal-fetal interface is presented in this topic review. Basic immunologic concepts are reviewed separately. (See "An overview of the innate immune system" and "The adaptive cellular immune response".)


The placenta and fetal membranes are directly exposed to maternal blood and tissues. Thus, unique features of the cells that comprise this interface must underlie the remarkable ability of the genetically distinct fetal tissue to inhabit the maternal host.

Not all immunologists studying reproduction agree that maternal immunity is solely antagonistic to trophoblast tissue. Alternative views have been expressed [11,12], some of which are described below. Indeed, a maternal immune presence in the decidua is essential for successful implantation [4]. Evidence of the opposite hypothesis (ie, that trophoblasts have offensive mechanisms for killing maternal lymphocytes) is also lacking. It is clear, however, that the placenta is normally protected from the killing functions of maternal cells. This protection may result from synthesis of soluble receptors (tumor necrosis factor [TNF]-alpha), display of nonfunctional receptors (Fas), and expression of decoy receptors (TNF-related apoptosis-inducing ligand [TRAIL] death domain-containing receptors DcR1 and DcR2) [13-16].

Fetal trophoblast cells — Fetal trophoblast cells are the specific cell layer that protects the embryo from those components of the maternal immune system dedicated to destroying foreign tissues. The inner cell mass and resultant embryo are secluded and protected beneath a layer of trophoblastic cells throughout pregnancy.


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  1. Hunt JS. Stranger in a strange land. Immunol Rev 2006; 213:36.
  2. Robertson SA. Immune regulation of conception and embryo implantation-all about quality control? J Reprod Immunol 2010; 85:51.
  3. Stoller M, Traupe T, Khattab AA, et al. Effects of coronary sinus occlusion on myocardial ischaemia in humans: role of coronary collateral function. Heart 2013; 99:548.
  4. Mor G, Abrahams VM. The immunology of pregnancy. In: Creasy and Resnik's Maternal-Fetal Medicine: Principles and Practice, 7th ed., Creasy RK, Resnik R, Iams JD, et al. (Eds), Elsevier, Philadelphia 2014. p.80.
  5. Guerin LR, Prins JR, Robertson SA. Regulatory T-cells and immune tolerance in pregnancy: a new target for infertility treatment? Hum Reprod Update 2009; 15:517.
  6. Leber A, Teles A, Zenclussen AC. Regulatory T cells and their role in pregnancy. Am J Reprod Immunol 2010; 63:445.
  7. Barrientos G, Tirado-González I, Klapp BF, et al. The impact of dendritic cells on angiogenic responses at the fetal-maternal interface. J Reprod Immunol 2009; 83:85.
  8. Dekel N, Gnainsky Y, Granot I, Mor G. Inflammation and implantation. Am J Reprod Immunol 2010; 63:17.
  9. Nagamatsu T, Schust DJ. The contribution of macrophages to normal and pathological pregnancies. Am J Reprod Immunol 2010; 63:460.
  10. Zhang J, Chen Z, Smith GN, Croy BA. Natural killer cell-triggered vascular transformation: maternal care before birth? Cell Mol Immunol 2011; 8:1.
  11. Matzinger P. The danger model: a renewed sense of self. Science 2002; 296:301.
  12. Mor G, Romero R, Aldo PB, Abrahams VM. Is the trophoblast an immune regulator? The role of Toll-like receptors during pregnancy. Crit Rev Immunol 2005; 25:375.
  13. Phillips TA, Ni J, Pan G, et al. TRAIL (Apo-2L) and TRAIL receptors in human placentas: implications for immune privilege. J Immunol 1999; 162:6053.
  14. Phillips TA, Ni J, Hunt JS. Death-inducing tumour necrosis factor (TNF) superfamily ligands and receptors are transcribed in human placentae, cytotrophoblasts, placental macrophages and placental cell lines. Placenta 2001; 22:663.
  15. Austgulen R, Johnsen H, Kjøllesdal AM, et al. Soluble receptors for tumor necrosis factor: occurrence in association with normal delivery at term. Obstet Gynecol 1993; 82:343.
  16. Payne SG, Smith SC, Davidge ST, et al. Death receptor Fas/Apo-1/CD95 expressed by human placental cytotrophoblasts does not mediate apoptosis. Biol Reprod 1999; 60:1144.
  17. Tilburgs T, Scherjon SA, Claas FH. Major histocompatibility complex (MHC)-mediated immune regulation of decidual leukocytes at the fetal-maternal interface. J Reprod Immunol 2010; 85:58.
  18. Le Bouteiller P, Mallet V. HLA-G and pregnancy. Rev Reprod 1997; 2:7.
  19. Hunt JS, Orr HT. HLA and maternal-fetal recognition. FASEB J 1992; 6:2344.
  20. Hunt JS, Langat DK, McIntire RH, Morales PJ. The role of HLA-G in human pregnancy. Reprod Biol Endocrinol 2006; 4 Suppl 1:S10.
  21. Petroff MG, Hunt JS. Immunity at the maternal-fetal interface. In: Mucosal immunology, 3rd ed, Mestecky J, Lamm ME, Strober W, et al (Eds), Academic Press, New York 2005. p.1735.
  22. Hunt JS, McIntire RH, Petroff MG. Immunobiology of human pregnancy. In: Knobil and Neill's physiology of reproduction, 3rd ed, Neill JD (Ed), Elsevier/Academic Press, St. Louis 2006. Vol 2, p.2759.
  23. Long EO. Regulation of immune responses through inhibitory receptors. Annu Rev Immunol 1999; 17:875.
  24. Shakhawat A, Shaikly V, Elzatma E, et al. Interaction between HLA-G and monocyte/macrophages in human pregnancy. J Reprod Immunol 2010; 85:40.
  25. Gregori S, Amodio G, Quattrone F, Panina-Bordignon P. HLA-G Orchestrates the Early Interaction of Human Trophoblasts with the Maternal Niche. Front Immunol 2015; 6:128.
  26. Tilburgs T, Evans JH, Crespo ÂC, Strominger JL. The HLA-G cycle provides for both NK tolerance and immunity at the maternal-fetal interface. Proc Natl Acad Sci U S A 2015; 112:13312.
  27. Zavazava N, Krönke M. Soluble HLA class I molecules induce apoptosis in alloreactive cytotoxic T lymphocytes. Nat Med 1996; 2:1005.
  28. Zavazava N. Soluble HLA class I molecules: biological significance and clinical implications. Mol Med Today 1998; 4:116.
  29. Fournel S, Aguerre-Girr M, Huc X, et al. Cutting edge: soluble HLA-G1 triggers CD95/CD95 ligand-mediated apoptosis in activated CD8+ cells by interacting with CD8. J Immunol 2000; 164:6100.
  30. Naji A, Durrbach A, Carosella ED, Rouas-Freiss N. Soluble HLA-G and HLA-G1 expressing antigen-presenting cells inhibit T-cell alloproliferation through ILT-2/ILT-4/FasL-mediated pathways. Hum Immunol 2007; 68:233.
  31. Hunt JS, Jadhav L, Chu W, et al. Soluble HLA-G circulates in maternal blood during pregnancy. Am J Obstet Gynecol 2000; 183:682.
  32. Morales PJ, Pace JL, Platt JS, et al. Synthesis of beta(2)-microglobulin-free, disulphide-linked HLA-G5 homodimers in human placental villous cytotrophoblast cells. Immunology 2007; 122:179.
  33. Köstlin N, Ostermeir AL, Spring B, et al. HLA-G promotes myeloid-derived suppressor cell accumulation and suppressive activity during human pregnancy through engagement of the receptor ILT4. Eur J Immunol 2016.
  34. Lee CL, Guo Y, So KH, et al. Soluble human leukocyte antigen G5 polarizes differentiation of macrophages toward a decidual macrophage-like phenotype. Hum Reprod 2015; 30:2263.
  35. van der Meer A, Lukassen HG, van Cranenbroek B, et al. Soluble HLA-G promotes Th1-type cytokine production by cytokine-activated uterine and peripheral natural killer cells. Mol Hum Reprod 2007; 13:123.
  36. Hunt JS, Fishback JL, Andrews GK, Wood GW. Expression of class I HLA genes by trophoblast cells. Analysis by in situ hybridization. J Immunol 1988; 140:1293.
  37. Hunt JS, Fishback JL, Chumbley G, Loke YW. Identification of class I MHC mRNA in human first trimester trophoblast cells by in situ hybridization. J Immunol 1990; 144:4420.
  38. Chu W, Fant ME, Geraghty DE, Hunt JS. Soluble HLA-G in human placentas: synthesis in trophoblasts and interferon-gamma-activated macrophages but not placental fibroblasts. Hum Immunol 1998; 59:435.
  39. Murphy SP, Tomasi TB. Absence of MHC class II antigen expression in trophoblast cells results from a lack of class II transactivator (CIITA) gene expression. Mol Reprod Dev 1998; 51:1.
  40. Petroff MG, Chen L, Phillips TA, et al. B7 family molecules are favorably positioned at the human maternal-fetal interface. Biol Reprod 2003; 68:1496.
  41. Munn DH, Zhou M, Attwood JT, et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 1998; 281:1191.
  42. Ban Y, Zhao Y, Liu F, et al. Effect of Indoleamine 2,3-Dioxygenase Expressed in HTR-8/SVneo Cells on Decidual NK Cell Cytotoxicity. Am J Reprod Immunol 2016; 75:519.
  43. Hunt JS, Chen HL, Miller L. Tumor necrosis factors: pivotal components of pregnancy? Biol Reprod 1996; 54:554.
  44. Runic R, Lockwood CJ, Ma Y, et al. Expression of Fas ligand by human cytotrophoblasts: implications in placentation and fetal survival. J Clin Endocrinol Metab 1996; 81:3119.
  45. Phillips TA, Ni J, Hunt JS. Cell-specific expression of B lymphocyte (APRIL, BLyS)- and Th2 (CD30L/CD153)-promoting tumor necrosis factor superfamily ligands in human placentas. J Leukoc Biol 2003; 74:81.
  46. Abrahams VM, Straszewski-Chavez SL, Guller S, Mor G. First trimester trophoblast cells secrete Fas ligand which induces immune cell apoptosis. Mol Hum Reprod 2004; 10:55.
  47. Frängsmyr L, Baranov V, Nagaeva O, et al. Cytoplasmic microvesicular form of Fas ligand in human early placenta: switching the tissue immune privilege hypothesis from cellular to vesicular level. Mol Hum Reprod 2005; 11:35.
  48. Kshirsagar SK, Alam SM, Jasti S, et al. Immunomodulatory molecules are released from the first trimester and term placenta via exosomes. Placenta 2012; 33:982.
  49. Mincheva-Nilsson L, Baranov V. The role of placental exosomes in reproduction. Am J Reprod Immunol 2010; 63:520.
  50. Redman CW, Sargent IL. Circulating microparticles in normal pregnancy and pre-eclampsia. Placenta 2008; 29 Suppl A:S73.
  51. Holder BS, Tower CL, Forbes K, et al. Immune cell activation by trophoblast-derived microvesicles is mediated by syncytin 1. Immunology 2012; 136:184.
  52. Delorme-Axford E, Donker RB, Mouillet JF, et al. Human placental trophoblasts confer viral resistance to recipient cells. Proc Natl Acad Sci U S A 2013; 110:12048.
  53. Holder B, Jones T, Sancho Shimizu V, et al. Macrophage Exosomes Induce Placental Inflammatory Cytokines: A Novel Mode of Maternal-Placental Messaging. Traffic 2016; 17:168.
  54. Denison FC, Kelly RW, Calder AA, Riley SC. Cytokine secretion by human fetal membranes, decidua and placenta at term. Hum Reprod 1998; 13:3560.
  55. Hunt JS. Cytokine networks in the human placenta. In: Cytokines in human reproduction, Hill JA (Ed), Wiley-Liss, New York 1999. p.203.
  56. Moreau P, Adrian-Cabestre F, Menier C, et al. IL-10 selectively induces HLA-G expression in human trophoblasts and monocytes. Int Immunol 1999; 11:803.
  57. Hennessy A, Pilmore HL, Simmons LA, Painter DM. A deficiency of placental IL-10 in preeclampsia. J Immunol 1999; 163:3491.
  58. Thaxton JE, Sharma S. Interleukin-10: a multi-faceted agent of pregnancy. Am J Reprod Immunol 2010; 63:482.
  59. Guo PF, Du MR, Wu HX, et al. Thymic stromal lymphopoietin from trophoblasts induces dendritic cell-mediated regulatory TH2 bias in the decidua during early gestation in humans. Blood 2010; 116:2061.
  60. Hsi BL, Hunt JS, Atkinson JP. Differential expression of complement regulatory proteins on subpopulations of human trophoblast cells. J Reprod Immunol 1991; 19:209.
  61. Holmes CH, Simpson KL, Okada H, et al. Complement regulatory proteins at the feto-maternal interface during human placental development: distribution of CD59 by comparison with membrane cofactor protein (CD46) and decay accelerating factor (CD55). Eur J Immunol 1992; 22:1579.
  62. Xu C, Mao D, Holers VM, et al. A critical role for murine complement regulator crry in fetomaternal tolerance. Science 2000; 287:498.
  63. Bulmer JN, Pace D, Ritson A. Immunoregulatory cells in human decidua: morphology, immunohistochemistry and function. Reprod Nutr Dev 1988; 28:1599.
  64. Gardner L, Moffett A. Dendritic cells in the human decidua. Biol Reprod 2003; 69:1438.
  65. King A, Wellings V, Gardner L, Loke YW. Immunocytochemical characterization of the unusual large granular lymphocytes in human endometrium throughout the menstrual cycle. Hum Immunol 1989; 24:195.
  66. Tilburgs T, Claas FH, Scherjon SA. Elsevier Trophoblast Research Award Lecture: Unique properties of decidual T cells and their role in immune regulation during human pregnancy. Placenta 2010; 31 Suppl:S82.
  67. Aldo PB, Racicot K, Craviero V, et al. Trophoblast induces monocyte differentiation into CD14+/CD16+ macrophages. Am J Reprod Immunol 2014; 72:270.
  68. Abrahams VM, Kim YM, Straszewski SL, et al. Macrophages and apoptotic cell clearance during pregnancy. Am J Reprod Immunol 2004; 51:275.
  69. Fest S, Aldo PB, Abrahams VM, et al. Trophoblast-macrophage interactions: a regulatory network for the protection of pregnancy. Am J Reprod Immunol 2007; 57:55.
  70. Harris LK. Review: Trophoblast-vascular cell interactions in early pregnancy: how to remodel a vessel. Placenta 2010; 31 Suppl:S93.
  71. Renaud SJ, Graham CH. The role of macrophages in utero-placental interactions during normal and pathological pregnancy. Immunol Invest 2008; 37:535.
  72. Tang Z, Abrahams VM, Mor G, Guller S. Placental Hofbauer cells and complications of pregnancy. Ann N Y Acad Sci 2011; 1221:103.
  73. Tang Z, Buhimschi IA, Buhimschi CS, et al. Decreased levels of folate receptor-β and reduced numbers of fetal macrophages (Hofbauer cells) in placentas from pregnancies with severe pre-eclampsia. Am J Reprod Immunol 2013; 70:104.
  74. Young OM, Tang Z, Niven-Fairchild T, et al. Toll-like receptor-mediated responses by placental Hofbauer cells (HBCs): a potential pro-inflammatory role for fetal M2 macrophages. Am J Reprod Immunol 2015; 73:22.
  75. Zhang J, Dunk C, Croy AB, Lye SJ. To serve and to protect: the role of decidual innate immune cells on human pregnancy. Cell Tissue Res 2016; 363:249.
  76. Kopcow HD, Allan DS, Chen X, et al. Human decidual NK cells form immature activating synapses and are not cytotoxic. Proc Natl Acad Sci U S A 2005; 102:15563.
  77. Croy BA, Luross JA, Guimond MJ, Hunt JS. Uterine natural killer cells: insights into lineage relationships and functions from studies of pregnancies in mutant and transgenic mice. Nat Immun 1997; 15:22.
  78. Parr EL, Chen HL, Parr MB, Hunt JS. Synthesis and granular localization of tumor necrosis factor-alpha in activated NK cells in the pregnant mouse uterus. J Reprod Immunol 1995; 28:31.
  79. Stallmach T, Ehrenstein T, Isenmann S, et al. The role of perforin-expression by granular metrial gland cells in pregnancy. Eur J Immunol 1995; 25:3342.
  80. Allen MP, Nilsen-Hamilton M. Granzymes D, E, F, and G are regulated through pregnancy and by IL-2 and IL-15 in granulated metrial gland cells. J Immunol 1998; 161:2772.
  81. Hunt JS, Miller L, Vassmer D, Croy BA. Expression of the inducible nitric oxide synthase gene in mouse uterine leukocytes and potential relationships with uterine function during pregnancy. Biol Reprod 1997; 57:827.
  82. Le Bouteiller P, Tabiasco J. Killers become builders during pregnancy. Nat Med 2006; 12:991.
  83. Hanna J, Goldman-Wohl D, Hamani Y, et al. Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nat Med 2006; 12:1065.
  84. Tabiasco J, Rabot M, Aguerre-Girr M, et al. Human decidual NK cells: unique phenotype and functional properties -- a review. Placenta 2006; 27 Suppl A:S34.
  85. Karimi K, Blois SM, Arck PC. The upside of natural killers. Nat Med 2008; 14:1184.
  86. Yagel S. The developmental role of natural killer cells at the fetal-maternal interface. Am J Obstet Gynecol 2009; 201:344.
  87. Lash GE, Robson SC, Bulmer JN. Review: Functional role of uterine natural killer (uNK) cells in human early pregnancy decidua. Placenta 2010; 31 Suppl:S87.
  88. Hiby SE, Walker JJ, O'shaughnessy KM, et al. Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success. J Exp Med 2004; 200:957.
  89. Hiby SE, Regan L, Lo W, et al. Association of maternal killer-cell immunoglobulin-like receptors and parental HLA-C genotypes with recurrent miscarriage. Hum Reprod 2008; 23:972.
  90. Management of high-risk pregnancy. In: Queenan's High-risk obstetrics, 6th ed, Queenan JT, Spong CY, Lockwood CJ (Eds), Blackwell Publishing Ltd., Malden, MA 2011.
  91. Moffett A, Hiby SE. How Does the maternal immune system contribute to the development of pre-eclampsia? Placenta 2007; 28 Suppl A:S51.
  92. Moffett A, Regan L, Braude P. Natural killer cells, miscarriage, and infertility. BMJ 2004; 329:1283.
  93. De Carolis C, Perricone C, Perricone R. NK cells, autoantibodies, and immunologic infertility: a complex interplay. Clin Rev Allergy Immunol 2010; 39:166.
  94. Krey G, Frank P, Shaikly V, et al. In vivo dendritic cell depletion reduces breeding efficiency, affecting implantation and early placental development in mice. J Mol Med (Berl) 2008; 86:999.
  95. Plaks V, Birnberg T, Berkutzki T, et al. Uterine DCs are crucial for decidua formation during embryo implantation in mice. J Clin Invest 2008; 118:3954.
  96. Collins MK, Tay CS, Erlebacher A. Dendritic cell entrapment within the pregnant uterus inhibits immune surveillance of the maternal/fetal interface in mice. J Clin Invest 2009; 119:2062.
  97. Huang SJ, Chen CP, Schatz F, et al. Pre-eclampsia is associated with dendritic cell recruitment into the uterine decidua. J Pathol 2008; 214:328.
  98. Lockwood CJ, Matta P, Krikun G, et al. Regulation of monocyte chemoattractant protein-1 expression by tumor necrosis factor-alpha and interleukin-1beta in first trimester human decidual cells: implications for preeclampsia. Am J Pathol 2006; 168:445.
  99. Heyborne KD, Cranfill RL, Carding SR, et al. Characterization of gamma delta T lymphocytes at the maternal-fetal interface. J Immunol 1992; 149:2872.
  100. Ito K, Karasawa M, Kawano T, et al. Involvement of decidual Valpha14 NKT cells in abortion. Proc Natl Acad Sci U S A 2000; 97:740.
  101. Mincheva-Nilsson L. Pregnancy and gamma/delta T cells: taking on the hard questions. Reprod Biol Endocrinol 2003; 1:120.
  102. Tilburgs T, Strominger JL. CD8+ effector T cells at the fetal-maternal interface, balancing fetal tolerance and antiviral immunity. Am J Reprod Immunol 2013; 69:395.
  103. Zenclussen AC. Adaptive immune responses during pregnancy. Am J Reprod Immunol 2013; 69:291.
  104. Mjösberg J, Berg G, Jenmalm MC, Ernerudh J. FOXP3+ regulatory T cells and T helper 1, T helper 2, and T helper 17 cells in human early pregnancy decidua. Biol Reprod 2010; 82:698.
  105. Tilburgs T, Crespo ÂC, van der Zwan A, et al. Human HLA-G+ extravillous trophoblasts: Immune-activating cells that interact with decidual leukocytes. Proc Natl Acad Sci U S A 2015; 112:7219.
  106. Rowe JH, Ertelt JM, Xin L, Way SS. Pregnancy imprints regulatory memory that sustains anergy to fetal antigen. Nature 2012; 490:102.
  107. Kahn DA, Baltimore D. Pregnancy induces a fetal antigen-specific maternal T regulatory cell response that contributes to tolerance. Proc Natl Acad Sci U S A 2010; 107:9299.
  108. Sasaki Y, Darmochwal-Kolarz D, Suzuki D, et al. Proportion of peripheral blood and decidual CD4(+) CD25(bright) regulatory T cells in pre-eclampsia. Clin Exp Immunol 2007; 149:139.
  109. Williams Z. Inducing tolerance to pregnancy. N Engl J Med 2012; 367:1159.
  110. Saito S, Nakashima A, Shima T, Ito M. Th1/Th2/Th17 and regulatory T-cell paradigm in pregnancy. Am J Reprod Immunol 2010; 63:601.
  111. Woidacki K, Zenclussen AC, Siebenhaar F. Mast cell-mediated and associated disorders in pregnancy: a risky game with an uncertain outcome? Front Immunol 2014; 5:231.
  112. Gomez-Lopez N, StLouis D, Lehr MA, et al. Immune cells in term and preterm labor. Cell Mol Immunol 2014; 11:571.
  113. Fettke F, Schumacher A, Costa SD, Zenclussen AC. B cells: the old new players in reproductive immunology. Front Immunol 2014; 5:285.
  114. Muzzio D, Zygmunt M, Jensen F. The role of pregnancy-associated hormones in the development and function of regulatory B cells. Front Endocrinol (Lausanne) 2014; 5:39.
  115. Lundell AC, Nordström I, Andersson K, et al. IFN type I and II induce BAFF secretion from human decidual stromal cells. Sci Rep 2017; 7:39904.
  116. Xu Y, Plazyo O, Romero R, et al. Isolation of Leukocytes from the Human Maternal-fetal Interface. J Vis Exp 2015; :e52863.
  117. Szekeres-Bartho J, Halasz M, Palkovics T. Progesterone in pregnancy; receptor-ligand interaction and signaling pathways. J Reprod Immunol 2009; 83:60.
  118. Szekeres-Bartho J, Wegmann TG. A progesterone-dependent immunomodulatory protein alters the Th1/Th2 balance. J Reprod Immunol 1996; 31:81.
  119. Miller L, Hunt JS. Regulation of TNF-alpha production in activated mouse macrophages by progesterone. J Immunol 1998; 160:5098.
  120. Wegmann TG, Lin H, Guilbert L, Mosmann TR. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today 1993; 14:353.
  121. Lin H, Mosmann TR, Guilbert L, et al. Synthesis of T helper 2-type cytokines at the maternal-fetal interface. J Immunol 1993; 151:4562.
  122. Wei SQ, Fraser W, Luo ZC. Inflammatory cytokines and spontaneous preterm birth in asymptomatic women: a systematic review. Obstet Gynecol 2010; 116:393.
  123. Romero R, Mazor M, Brandt F, et al. Interleukin-1 alpha and interleukin-1 beta in preterm and term human parturition. Am J Reprod Immunol 1992; 27:117.
  124. Romero R, Mazor M, Sepulveda W, et al. Tumor necrosis factor in preterm and term labor. Am J Obstet Gynecol 1992; 166:1576.
  125. Mor G. Pregnancy reconceived: what keeps a mother's immune system from treating her baby as foreign tissue? A new theory resolves the paradox. Nat Hist 2007; 116:36. http://findarticles.com/p/articles/mi_m1134/is_4_116/ai_n19187208/ (Accessed on June 25, 2012).
  126. Nancy P, Tagliani E, Tay CS, et al. Chemokine gene silencing in decidual stromal cells limits T cell access to the maternal-fetal interface. Science 2012; 336:1317.
  127. Salamonsen LA, Hannan NJ, Dimitriadis E. Cytokines and chemokines during human embryo implantation: roles in implantation and early placentation. Semin Reprod Med 2007; 25:437.
  128. Luppi P, Haluszczak C, Betters D, et al. Monocytes are progressively activated in the circulation of pregnant women. J Leukoc Biol 2002; 72:874.
  129. Amoudruz P, Minang JT, Sundström Y, et al. Pregnancy, but not the allergic status, influences spontaneous and induced interleukin-1beta (IL-1beta), IL-6, IL-10 and IL-12 responses. Immunology 2006; 119:18.
  130. Denney JM, Nelson EL, Wadhwa PD, et al. Longitudinal modulation of immune system cytokine profile during pregnancy. Cytokine 2011; 53:170.
  131. Veenstra van Nieuwenhoven AL, Bouman A, Moes H, et al. Endotoxin-induced cytokine production of monocytes of third-trimester pregnant women compared with women in the follicular phase of the menstrual cycle. Am J Obstet Gynecol 2003; 188:1073.
  132. Sacks GP, Redman CW, Sargent IL. Monocytes are primed to produce the Th1 type cytokine IL-12 in normal human pregnancy: an intracellular flow cytometric analysis of peripheral blood mononuclear cells. Clin Exp Immunol 2003; 131:490.
  133. Tafuri A, Alferink J, Möller P, et al. T cell awareness of paternal alloantigens during pregnancy. Science 1995; 270:630.
  134. Somerset DA, Zheng Y, Kilby MD, et al. Normal human pregnancy is associated with an elevation in the immune suppressive CD25+ CD4+ regulatory T-cell subset. Immunology 2004; 112:38.
  135. Aluvihare VR, Kallikourdis M, Betz AG. Regulatory T cells mediate maternal tolerance to the fetus. Nat Immunol 2004; 5:266.
  136. Zenclussen AC, Gerlof K, Zenclussen ML, et al. Abnormal T-cell reactivity against paternal antigens in spontaneous abortion: adoptive transfer of pregnancy-induced CD4+CD25+ T regulatory cells prevents fetal rejection in a murine abortion model. Am J Pathol 2005; 166:811.
  137. Schumacher A, Wafula PO, Bertoja AZ, et al. Mechanisms of action of regulatory T cells specific for paternal antigens during pregnancy. Obstet Gynecol 2007; 110:1137.
  138. Chaouat G, Assal Meliani A, Martal J, et al. IL-10 prevents naturally occurring fetal loss in the CBA x DBA/2 mating combination, and local defect in IL-10 production in this abortion-prone combination is corrected by in vivo injection of IFN-tau. J Immunol 1995; 154:4261.
  139. Svensson L, Arvola M, Sällström MA, et al. The Th2 cytokines IL-4 and IL-10 are not crucial for the completion of allogeneic pregnancy in mice. J Reprod Immunol 2001; 51:3.
  140. Rolle L, Memarzadeh Tehran M, Morell-García A, et al. Cutting edge: IL-10-producing regulatory B cells in early human pregnancy. Am J Reprod Immunol 2013; 70:448.
  141. Christiansen OB, Nielsen HS, Kolte AM. Future directions of failed implantation and recurrent miscarriage research. Reprod Biomed Online 2006; 13:71.
  142. Robertson SA, O'Leary S, Armstrong DT. Influence of semen on inflammatory modulators of embryo implantation. Soc Reprod Fertil Suppl 2006; 62:231.
  143. Chalubinski M, Kowalski ML. Endocrine disrupters--potential modulators of the immune system and allergic response. Allergy 2006; 61:1326.
  144. Martius J, Eschenbach DA. The role of bacterial vaginosis as a cause of amniotic fluid infection, chorioamnionitis and prematurity--a review. Arch Gynecol Obstet 1990; 247:1.
  145. Gibbs RS, Romero R, Hillier SL, et al. A review of premature birth and subclinical infection. Am J Obstet Gynecol 1992; 166:1515.
  146. Cardenas I, Means RE, Aldo P, et al. Viral infection of the placenta leads to fetal inflammation and sensitization to bacterial products predisposing to preterm labor. J Immunol 2010; 185:1248.
  147. Abrahams VM. Pattern recognition at the maternal-fetal interface. Immunol Invest 2008; 37:427.
  148. Abrahams VM. The role of the Nod-like receptor family in trophoblast innate immune responses. J Reprod Immunol 2011; 88:112.
  149. Mowbray JF, Gibbings C, Liddell H, et al. Controlled trial of treatment of recurrent spontaneous abortion by immunisation with paternal cells. Lancet 1985; 1:941.
  150. Ober C, Hyslop T, Hauck WW. Inbreeding effects on fertility in humans: evidence for reproductive compensation. Am J Hum Genet 1999; 64:225.
  151. Ober C, Hyslop T, Elias S, et al. Human leukocyte antigen matching and fetal loss: results of a 10 year prospective study. Hum Reprod 1998; 13:33.
  152. Ober C, Karrison T, Odem RR, et al. Mononuclear-cell immunisation in prevention of recurrent miscarriages: a randomised trial. Lancet 1999; 354:365.
  153. Stephenson MD, Fluker MR. Treatment of repeated unexplained in vitro fertilization failure with intravenous immunoglobulin: a randomized, placebo-controlled Canadian trial. Fertil Steril 2000; 74:1108.
  154. Matthiesen L, Kalkunte S, Sharma S. Multiple pregnancy failures: an immunological paradigm. Am J Reprod Immunol 2012; 67:334.
  155. Cervera R, Balasch J. Autoimmunity and recurrent pregnancy losses. Clin Rev Allergy Immunol 2010; 39:148.
  156. Girardi G, Berman J, Redecha P, et al. Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome. J Clin Invest 2003; 112:1644.
  157. Girardi G, Redecha P, Salmon JE. Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation. Nat Med 2004; 10:1222.
  158. Berman J, Girardi G, Salmon JE. TNF-alpha is a critical effector and a target for therapy in antiphospholipid antibody-induced pregnancy loss. J Immunol 2005; 174:485.
  159. Redecha P, Tilley R, Tencati M, et al. Tissue factor: a link between C5a and neutrophil activation in antiphospholipid antibody induced fetal injury. Blood 2007; 110:2423.
  160. Tincani A, Cavazzana I, Ziglioli T, et al. Complement activation and pregnancy failure. Clin Rev Allergy Immunol 2010; 39:153.
  161. Girardi G. Role of tissue factor in the maternal immunological attack of the embryo in the antiphospholipid syndrome. Clin Rev Allergy Immunol 2010; 39:160.
  162. Mulla MJ, Brosens JJ, Chamley LW, et al. Antiphospholipid antibodies induce a pro-inflammatory response in first trimester trophoblast via the TLR4/MyD88 pathway. Am J Reprod Immunol 2009; 62:96.
  163. Mulla MJ, Myrtolli K, Brosens JJ, et al. Antiphospholipid antibodies limit trophoblast migration by reducing IL-6 production and STAT3 activity. Am J Reprod Immunol 2010; 63:339.
  164. Carroll TY, Mulla MJ, Han CS, et al. Modulation of trophoblast angiogenic factor secretion by antiphospholipid antibodies is not reversed by heparin. Am J Reprod Immunol 2011; 66:286.
  165. Mulla MJ, Salmon JE, Chamley LW, et al. A role for uric acid and the Nalp3 inflammasome in antiphospholipid antibody-induced IL-1β production by human first trimester trophoblast. PLoS One 2013; 8:e65237.
  166. Hunt JS, Robertson SA. Uterine macrophages and environmental programming for pregnancy success. J Reprod Immunol 1996; 32:1.
  167. Mold JE, Michaëlsson J, Burt TD, et al. Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero. Science 2008; 322:1562.
  168. Hoftman AC, Hernandez MI, Lee KW, Stiehm ER. Newborn illnesses caused by transplacental antibodies. Adv Pediatr 2008; 55:271.
  169. Fons P, Chabot S, Cartwright JE, et al. Soluble HLA-G1 inhibits angiogenesis through an apoptotic pathway and by direct binding to CD160 receptor expressed by endothelial cells. Blood 2006; 108:2608.
  170. Nicolae D, Cox NJ, Lester LA, et al. Fine mapping and positional candidate studies identify HLA-G as an asthma susceptibility gene on chromosome 6p21. Am J Hum Genet 2005; 76:349.
  171. Girardi G, Yarilin D, Thurman JM, et al. Complement activation induces dysregulation of angiogenic factors and causes fetal rejection and growth restriction. J Exp Med 2006; 203:2165.
  172. Buhimschi CS, Weiner CP, Buhimschi IA. Proteomics, part II: the emerging role of proteomics over genomics in spontaneous preterm labor/birth. Obstet Gynecol Surv 2006; 61:543.
  173. Abrahams VM. Antagonizing toll-like receptors to prevent preterm labor. Reprod Sci 2008; 15:108.